The present invention relates to methods for the prevention of adhesions, excessive scar formation and other types of abnormal proliferation of tissue using angiogenesis inhibitors.
Scars are the result of wounds that have healed, lesions due to diseases, or surgical operations. Hypertrophic and keloid scars occur when the tissue response is out of proportion to the amount of scar tissue required for normal repair and healing. A keloid scar is a raised, firm, thickened red scar that exceeds the boundary of the injury and may grow for a prolonged period of time. The increase in scar size is due to deposition of all increased amount of collagen into the tissue. African-Americans are genetically prone to developing keloids. Keloid development has been associated with different types of skin injury including surgery, ear piercing, laceration, burns, vaccination or inflammatory process. Common sites are earlobes and the upper trunk and extremities. Surgical removal of keloids alone has been associated with a recurrence rate of 45% to 100%.
The problem of excessive scar formation that manifests itself clinically is a multi-billion dollar problem. For example, intra-abdominal adhesions results in a very significant morbidity and mortality in every surgery practice. Greater than 400,000 hospital admissions in the United States per year are for treatment of pelvic adhesions following surgery. Repeat surgery can greatly aggravate scarring.
There is no effective treatment to prevent adhesions, although numerous different technologies have been tried, including application of barriers which are designed to avoid direct tissue to tissue interactions, and administration of immunosuppressants to decrease inflammatory reactions. Currently there is only one product approved by the FDA for intra-abdominal and one product approved by the FDA for pelvic adhesions. These are principally mechanical barriers to adhesion formation. They are only minimally effective clinically and there remains a huge demand for an alternative. Keloids have been treated with injection of corticosteroid into the scar, by laser therapy, and by administration of pharmacologic agents that interfere with collagen synthesis. Numerous treatments after excision have been used, such as postexcisional injections of corticosteroids or interferon, silicone sheeting, radiotherapy, and pressure splints or garments. See, for example, Berman, et al., J. Am. Acad. Dermatol. 33, 117-123 (1995); Pulton, Dermatol. Surg. 21, 947-951 (1995); Cosman, et al., Plast. Reconstr. Surg. 53, 540-543 (1974); Rockwell, et al., Plast. Reconstr. Surg. 827-835 (1989); Griffin, et al., Plast. Reconstr. Surg. 46, 145-150 (1970); Bisley, et al., J. Am. Acad. Dermatol. 35, 113-114 (1996); Klumper, et al., J. Acad. Dermatol. 31, 225-231 (1994); Larrabee, et al., Arch. Otolaryngol. Head Neck Surg. 116, 1159-1162 (1990); Darzi, et al., J. Plast. Surg. 45, 374-379 (1992); and Berman, et al., J. Am. Acad. Dermatol. 37, 755-757 (1997).
It is therefore an object of the present invention to provide a treatment for prevention of excessive scarring and adhesions, without the inhibition of wound healing.
A method and compositions for inhibiting excessive scar formation and adhesions by administering to a patient in need thereof an effective amount of an angiogenesis inhibitor. In the preferred embodiment, the angiogenesis inhibitor is selective, such as a fumagillol derivative like 0-chloroacetylcarbamoyl-Fumagillol (TNP-470, TAP Pharmaceuticals), thalidomide, or a selective drug having more than one activity, such as minocycline or penicilliamine which also have antibiotic activity. Less selective compounds can also be used, such as the cytokine IL12. Patients to be treated include those having experienced trauma, surgical intervention, burns, and other types of injuries. The inhibitor is administered in an amount effective to decrease excessive scarring, defined as formation of high density tissue including cells and connective tissue, without preventing normal wound closure. The inhibitors can be administered systemically and/or locally or topically, as needed. For prevention of adhesions, the angiogenesis inhibitor would typically be applied at the time of surgery, preferably in a controlled release formulation and/or using barrier technology.